Method of treating post-surgical acute pain

ABSTRACT

A method is provided for treating pain in patients recovering from post-surgical trauma by administering between about 13 to about 30 mg of diclofenac potassium in a liquid dispersible formulation over a period of at least 24 hours, wherein the daily total amount of diclofenac potassium administered is less than or equal to about 100 mg. The method is particularly useful in treating acute pain in bunionectomy patients.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority from U.S. Provisionalapplication Ser. No. 61/055,581, filed May 23, 2008, which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a method for treating acute pain in apatient recovering from post-surgical trauma which employs an orallyadministered low dose amount of diclofenac potassium in a dispersibleliquid formulation. Specifically, the present invention relates to amethod for treating acute pain in patients recovering from abunionectomy which utilizes an orally administered low dose amount ofdiclofenac potassium in a dispersible liquid formulation.

BACKGROUND OF THE INVENTION

Pain is an unpleasant sensory and emotional experience arising fromactual or potential tissue damage. Pain is highly subjective to theindividual experiencing it, but medical diagnosis is based oncharacterising it in various ways such as the duration, severity, type(dull, burning or stabbing), and location in body. Experiencing pain isinfluenced by a number of dynamic, changing and interacting physical,mental, biochemical, physiological, psychological, social, cultural andemotional factors. Thus, pain perceived as intense at one time may atanother time be perceived as less intense although all other factorsappear to be constant.

Pain management divides symptoms into acute or chronic pain. Acute painis distinguished from chronic pain. Acute pain warns the patient thatsomething is wrong, and may result from a variety of causes includingtissue damage, infection and/or inflammation. Chronic pain, on the otherhand, may have no apparent cause or may be caused by a developingillness or imbalance. Sometimes chronic pain can have a psychosomatic orpsychogenic cause.

Surgical procedures often result in some form of acute pain. Surgicalpain may include nociceptive, neuropathic or psychological components.Nociceptive pain is a pain experienced as a result of nociception, whichis detection of a stimulus by a pain receptor (nociceptor) andtransmission of the information to the brain along nerves. Nociceptivepain is caused by tissue damage and inflammation in response to trauma.The resulting pain is usually not well localized and is opioidresponsive.

The goal of post-surgical pain management is twofold: i) to provide aquick onset of analgesic or pain relief and ii) to reduce or modulatethe quality and intensity of pain a patient experiences in thepost-surgical period. The improvement in minimally invasive surgicaltechniques has resulted in a reduction in patient time in a hospital andhas shifted many procedures to the physician's office. Outpatientsurgery has become a procedure of choice for many simple to complexprocedures, such as bunionectomy, knee surgery, hernia repair,tonsillectomy, carpel tunnel release, cataract removal, hysterectomy andprostatectomy. The patient must now be made comfortable enough in ashort period of time to return home and safely manage his or her ownpain. Medications that provide gradual but extended response to acutepain situation are often inappropriate in this situation. Treatment foracute pain after bunionectomy surgery typically consists of opioidand/or NSAIDs/COX-2 inhibitors. In some cases, opioids are given forseveral days and then the subject is treated with an NSAID or COX-2Inhibitor. However, interest in the cardiovascular risk associated withthe use of COX-2 inhibitors has become intense, especially in regard torofecoxib and celecoxib. While current treatments for management ofpost-surgical acute pain are useful, there is a need for improvedmethods for treating post-surgical acute pain, particularly followingbunionectomy, which provides immediate relief of acute pain with littleor no risk of a cardiovascular event.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts mean NPRS pain intensity scores over time during the48-hour multiple dose period (Full Analysis Population)

FIG. 2 depicts Day 1 mean PID scores over time (Full AnalysisPopulation)

SUMMARY OF THE INVENTION

In a first aspect, the invention provides a method of treating acutepost-surgical pain, e.g., osteotomy pain, in a patient in need of suchtreatment, said method comprising the step of orally administering tothe patient a dose of between about 13 to about 30 mg of diclofenacpotassium in an liquid dispersible formulation every 4 hours to 8 hoursover a period of at least 24 hours, wherein the daily total amount ofdiclofenac potassium administered is less than or equal to about 100 mg.

In one embodiment of the first aspect, the pain results from abunionectomy.

In another embodiment of the first aspect, internal fixation may beperformed during the bunionectomy.

In a second aspect, the invention provides a method of treating acutepost-bunionectomy pain in a patient in need of such treatment, saidmethod comprising orally administering to the patient a dose of betweenabout 13 to about 30 mg of diclofenac potassium in a dispersible liquidformulation every 4 hours to 8 hours over a period of at least 24 hours,wherein the daily total amount of diclofenac potassium administered isless than or equal to about 100 mg.

In one embodiment of the second aspect, internal fixation may beperformed during the bunionectomy.

In one embodiment of either aspect, the diclofenac potassium in thedispersible liquid formulation is administered about every 5 hours toabout 8 hours.

In another embodiment of either aspect, the diclofenac potassium in thedispersible liquid formulation is administered about every 6 hours.

In another embodiment of either aspect, the diclofenac potassium in thedispersible liquid formulation is administered over a period of at leastabout 30 hours.

In another embodiment of either aspect, the diclofenac potassium in thedispersible liquid formulation is administered over a period of at leastabout 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours orseven days.

In another embodiment of either aspect, the amount of the diclofenacpotassium in the dispersible liquid formulation comprises at least about13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg,17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg,28 mg, or 30 mg of diclofenac potassium.

In another embodiment of either aspect, the administered amount ofdiclofenac potassium in the dispersible liquid formulation is effectivefor treating the pain for about 6 to about 8 hours after administration.

In another embodiment of either aspect, the plasma concentration ofdiclofenac in a patient ranges between about 670 to about 1500 ng/ml inless than 30 minutes with the concomitant onset of relief of acute pain.

In another embodiment of either aspect, the administration of diclofenacpotassium in the dispersible liquid formulation results in immediateincrease in plasma concentration of diclofenac characterized by T(max)of 0.47 hours.

In another embodiment of either aspect, diclofenac is substantiallyeliminated from plasma in the first 2 hours following administration.

In another embodiment of either aspect, the amount of the diclofenacpotassium in the dispersible liquid formulation comprises about 25 mg ofdiclofenac potassium.

In another embodiment of either aspect, the administration of diclofenacpotassium in the dispersible liquid formulation results in an average 48hour NPRS pain score of about 2.49.

In another embodiment of either aspect, the administration of diclofenacpotassium in the dispersible liquid formulation results in a median timeto onset of greater than or equal to 30% pain reduction of about 60minutes in a 6 to 8 hour initial dosing period.

In another embodiment of either aspect, the administration of diclofenacpotassium in the dispersible liquid formulation provides a median timeto onset of meaningful pain relief of about 70 minutes in a 6 to 8 hourinitial dosing period.

In another embodiment of either aspect, the administration of diclofenacpotassium in the dispersible liquid formulation provides clinicallysignificant analgesic efficacy for about 6 hours.

In another embodiment of either aspect, 25 mg of diclofenac potassium inthe dispersible liquid formulation is administered four times over aperiod of about 24 hours.

In another embodiment of either aspect, the diclofenac potassium in thedispersible liquid formulation is contained in a capsule such as a softor hard gelatin capsule.

In another embodiment of either aspect, no opioid is co-administeredwith the diclofenac potassium in the dispersible liquid formulation.

In another embodiment of either aspect, the acute pain comprises mild tomoderate pain, moderate to moderately severe pain, or moderate to severepain.

These and other embodiments of the invention will become apparent inlight of the detailed description below.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for treating acute pain inpatients recovering from post-surgical trauma such as that resultingfrom osteotomy. The method is particularly useful in treating acute painin patients that have undergone outpatient surgical procedures such asbunionectomy. The method comprises orally administering between about 13to about 30 mg, e.g., about 25 mg, of diclofenac potassium in adispersible liquid formulation about every four hours to 8 hours for aperiod of at least 24 hours, wherein the daily total amount ofdiclofenac potassium administered is less than or equal to about 100 mg.

The method is based on the surprising discovery that post-surgicalanalgesia, particularly post-osteotomy analgesia, can be achieved,without the need for opioids, with a relatively low oral dose (e.g.,between about 13 mg to about 30 mg) of diclofenac potassium in adispersible liquid formulation. Surgical procedures, such asbunionectomy, that are typically performed as an outpatient procedurehave a preferential need for post-surgical analgesic methods that can beadministered without substantial patient overview. Consequently, use ofanalgesics that affect, inter alia, motor functions, such as opioids,are not desirable for management of post-surgical pain after anoutpatient surgical procedure. The post-surgical analgesia achieved witha low oral dose dispersant liquid diclofenac potassium preparationprovides sufficient analgesia to delay or suspend the use of an opioidin the treatment of acute post-surgical pain, and is, therefore, aneffective method of pain management after an outpatient surgicalprocedure. The method of the invention surprisingly provided effectivepain relief for patients who had undergone osteotomy, e.g., bunionectomysurgery, without an increased risk of a treatment related adverse eventrelative to the control.

All publications, patent applications, patents and other referencesmentioned herein, if not otherwise indicated, are explicitlyincorporated by reference herein in their entirety for all purposes asif fully set forth.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. In case of conflict, thepresent specification, including definitions, will control.

Except where expressly noted, trademarks are shown in upper case.

Unless stated otherwise, all percentages, parts, ratios, etc., are byweight.

When an amount, concentration, or other value or parameter is given as arange, or a list of upper and lower values, this is to be understood asspecifically disclosing all ranges formed from any pair of any upper andlower range limits, regardless of whether ranges are separatelydisclosed. Where a range of numerical values is recited herein, unlessotherwise stated, the range is intended to include the endpointsthereof, and all integers and fractions within the range. It is notintended that the scope of the present invention be limited to thespecific values recited when defining a range.

When the term “about” is used in describing a value or an end-point of arange, the invention should be understood to include the specific valueor end-point referred to.

As used herein, the terms “comprises,” “comprising,” “includes,”“including,” “has,” “having” or any other variation thereof, areintended to cover a non-exclusive inclusion. For example, a process,method, article, or apparatus that comprises a list of elements is notnecessarily limited to only those elements but can include otherelements not expressly listed or inherent to such process, method,article, or apparatus. Further, unless expressly stated to the contrary,“or” refers to an inclusive or and not to an exclusive or. For example,a condition A or B is satisfied by any one of the following: A is true(or present) and B is false (or not present), A is false (or notpresent) and B is true (or present), and both A and B are true (orpresent).

The use of “a” or “an” to describe the various elements and componentsherein is merely for convenience and to give a general sense of theinvention. This description should be read to include one or at leastone and the singular also includes the plural unless it is obvious thatit is meant otherwise.

Diclofenac Potassium in a Dispersible Liquid Formulation:

The present invention relates to a method for treating acute pain suchas that resulting from an osteotomy, e.g., a bunionectomy, based on useof an oral dispersible liquid formulation comprising diclofenacpotassium and at least one pharmaceutically acceptable, non-toxicdispersing agent. A particularly useful dispersible liquid formulationof diclofenac potassium is described in U.S. Pat. No. 6,365,180, whichis hereby incorporated by reference in its entirety. Another usefulorally administered dispersible liquid formulation of diclofenacpotassium, based on the use of a bicarbonate dispersing agent, isdescribed in U.S. Pat. No. 6,974,595 (i.e., Examples 6 and 7), which isincorporated by reference in its entirety. Diclofenac(potassium[2-(2,6-dichlorophenyl) amino]-phenyl]acetate), is a potentnonsteroidal anti-inflammatory (NASID) drug therapeutically used ininflammatory conditions and as an analgesic. Like other NASIDs,diclofenac interacts with the arachidonic acid cascade at the level ofcyclo-oxygenase. Diclofenac inhibits cyclo-oxygenase at micromolarconcentrations and as a consequence the formation of thromboxanes,prostaglandins and prostacyclin is inhibited under various clinical andexperimental conditions. As used herein, the term “pharmaceuticallyacceptable,” when referring to any or all components of the presentcompositions, means that such component(s) are compatible with othercomponents therein, and not deleterious to the recipient thereof.

A dispersing agent is a surface-active substance added to a suspension,usually a colloid, to improve the separation of particles and to preventsettling or clumping in the gastrointestinal tract by facilitatingdistribution of particles or droplets throughout the gastrointestinaltract. Any pharmaceutically acceptable dispersing agents may be used,including, for example, alkali metal bicarbonates or mixtures thereof,such as potassium bicarbonate in amount 20-80% by weight of the weightof diclofenac; the polymer-based dispersing agents which include, forexample, polyvinylpyrrolidone (PVP; commercially known as Plasdone™);and the carbohydrate-based dispersing agents such as, for example,hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), andthe cyclodextrins. Useful dispersing agents include PVP K29-32,dextrins, starch, derivatized starch and dextrans, while of thedextrins, derivatized cyclodextrins are especially useful. Of suchcyclodextrins, hydroxypropyl beta-cyclodextrin and gamma-cyclodextrinare especially preferred. The numbers relate to the molecular weight ofthe polymer wherein, for example, PVP K-30 has an average molecularweight of about 30,000, with attendant viscosity characteristics.

The dispersible liquid formulation further comprises at least onepharmaceutically acceptable non-toxic solubilizing agent. Such readilyavailable solubilizing agents are well known in the art and is typicallyrepresented by the family of compounds known as polyethylene glycols(PEG) having molecular weights from about 200 to about 8,000. For liquidformulations used for filling soft capsules such as soft gelatincapsules, suitable molecular weights range from about 200 to about 600with PEG 400 being especially useful. Another example of suitablesolubilizing agent includes sorbitol.

Optionally, another solubilizing agent which may be utilized incompositions of the present invention is water, especially purified anddeionized water. For such compositions, the concentration of water isfrom about zero percent to about ninety-nine percent (w/w). Moreparticularly for compositions of the present invention to be filled intosoft capsules, a maximum water concentration from about 0% to about 5%is preferred, although the concentration of total solubilizing agent maybe the full concentration range taught herein.

As used in the present compositions, the concentration of the sum ofsolubilizing agent utilized, wherein more than one solubilizing agentcan be utilized, is from about 0 percent to about 99 percent (w/w). Thepreferred concentration of solubilizing agent in the presentcompositions is from about 60 percent to about 90 percent (w/w).

If the dispersible liquid formulations are to be filled in soft gelatincapsules, is at least one optional pharmaceutically acceptable,non-toxic plasticizing agent may be used. Such plasticizing agents,which are well known in the pharmaceutical formulation art, include, forexample, glycerin, propylene glycol, and sorbitol. Such commerciallyavailable plasticizers can be prepared to include more than oneplasticizing agent component, but the preferred plasticizing agent forthe present compositions is glycerin. In addition to its use as aplasticizing agent, propylene glycol can be used as a solubilizing agentwhen used alone or in combination with another solubilizing agent astaught herein.

As used in the present invention, the concentration of the sum ofplasticizing agent utilized, wherein more than one plasticizing agentcan be utilized, is from about zero percent to about 75 percent (w/w).The preferred of plasticizing agent is from about zero percent (0%) toabout fifty percent (50%), and an especially preferred concentration ina range from about one percent (1%) to about thirty percent (30%). Whenthe compositions of the present invention are used to fill soft gelatincapsules, the general concentration of such plasticizing agent rangesfrom about 5 percent to about 10 percent (w/w). Such plasticizers areespecially useful with soft gelatin capsule preparations because,without which, such capsules tend to harden and lose their beneficialproperties by, potentially, cracking or becoming brittle.

Another optional component of the present compositions, which is apreferred component, is at least one pharmaceutically acceptable,non-toxic, surfactant, preferably a non-ionic surfactant. Suchsurfactants are well known in the pharmaceutical formulation art andinclude readily available surfactants having a concentration from aboutzero percent to about 90 percent such as, for example, macro gel esters(Labrafils), Tandem 522™, Span 80™, Gelucieres™, such as, for example,tocopherol polyethylene glycol 1000 succinate, polysorbate 20, andpolysorbate 80. Of these, polysorbate 20 and polysorbate 80 areparticularly useful. The addition of at least one surfactant,particularly a non-ionic as described above, to the liquid compositionsof the present invention, improves the dispersion properties ofdiclofenac potassium relative to compositions not containing suchnon-ionic surfactant. This in turn provides a more rapid onset of thetherapeutic benefits provided by diclofenac potassium with reducedgastroirritation in a mammal relative to compositions not containing thesurfactant.

As used in the present invention, the concentration of the sum ofnon-ionic surfactant utilized, wherein more than one such surfactant canbe utilized, generally ranges from about zero percent to about 10percent (w/w), with a range from about 1 percent to about 5 percent(w/w) being preferred. A particularly useful concentration is about 3percent (w/w).

Typically, the order of addition of the various components comprisingthe present invention will not affect the formation of a solution, whendesired, of the present invention. However, when such a surfactant isused, it may be best to add the surfactant or surfactants followingaddition of diclofenac active ingredient and dispersing agent.

It should be understood that each component comprising the compositionsof the present invention must be pharmaceutically acceptable andutilized in a non-toxic concentration. Other pharmaceuticallyacceptable, non-toxic pharmaceutical additives may be included in thecompositions of the present invention and include, for example,sweetening agents, local anesthetics, antibacterials, a lower alkylalcohol such as ethanol, and the like.

Commonly used pharmaceutical agents, such as, for example, about 0.1 Nto 6N hydrochloric acid, are used in the liquid formulation as astabilizing agent for softgel capsule. A preferred pH range of thepresent compositions when used for filling soft gelatin capsules is fromabout 4.0 to about 9.0.

The resulting oral administrable composition comprising diclofenacpotassium in a dispersible liquid formulation exhibits improveddispersing properties of the diclofenac potassium upon contact withstomach acid, which results in faster, reproducible, and a more uniformabsorption rate than conventional pharmaceutical compositions. A morerapid, uniform absorption of the diclofenac potassium generally providesa more rapid onset of the therapeutic benefits.

The oral dispersible liquid formulations of the present invention areusually formulated to deliver a dosage level of between about 13 toabout 30 mg, usually between about 14 mg to about 25 mg, of diclofenacpotassium for total dosage amount of up to about 100 mg per day. Thisformulation may also be used to fill capsules such as hard or softgelatin capsules. The preparation of such capsules is well known in thepharmaceutical art [see, e.g. Modem Pharmaceutics, Third Edition, (G. S.Banker and C. T. Rhodes, ed.; 1996); and The Theory and Practice ofIndustrial Pharmacy, Third Edition, (L. Lachman, H. A. Liebernan, and J.L. Kanig, ed.; 1986)].

Pain Management after Bunionectomy:

A bunion or hallux valgus is an inflammation or thickening of the jointcapsule of the great toe. This inflammation causes injury and deformityto the joint due to abnormal bone growth. The great toe is forced intoward the rest of the toes, causing the head of the first metatarsalbone to jut out and rub against the side of the shoe; the underlyingtissue becomes inflamed and a painful growth forms. As this bony growthdevelops, the bunion is formed as the big toe is forced to grow at anincreasing angle towards the rest of the toes. A bunion may also developin the fifth metatarsal bone, in which case it is known as a bunionetteor tailor's bunion. Bunions often develop from wearing narrow,high-heeled shoes with pointed toes, which puts enormous pressure on thefront of the foot and causes the foot and toes to rest at unnaturalangles. Injury in the joint may also cause a bunion to develop overtime. Genetics play a factor in 10% to 15% of all bunion problems; oneinherited deformity, hallux valgus, causes the bone and joint of the bigtoe to shift and grow inward, so that the second toe crosses over it.Flat feet, gout, and arthritis increase the risk for bunions.

Bunion surgery, usually called a bunionectomy, is almost always done asan outpatient procedure. The procedure itself varies depending on thetype and severity of the deformity. Although the procedure varies, therecovery is the same for all. Some of the bunionectomy procedures arenamed Akin, Austin Akin, Keller, Silver, Silver Akin, and Kalishdepending on which area of the bone is cut and the type of cut that ismade. Once the subject is in the operating room and after anesthesia hasbeen started, a tourniquet is applied to either the thigh or ankledepending on the type of anesthesia. The tourniquet is used to preventbleeding during surgery. After the tourniquet is applied, the foot andlower leg are washed in a sterile fashion to help prevent infection. Thesurgeon then makes an incision at the top of the great toe into thejoint capsule.

Once the bone is exposed, the surgeon makes a cut in the bone in orderto correct the deformity. This is called an “osteotomy”. As definedherein, an osteotomy is a surgical procedure in which a bone is cut toshorten, lengthen or change its alignment. It is used for example tostraighten a bone that has healed crookedly following a fracture. Boneis defined herein as a connective tissue consisting of bone-buildingosteoblasts, stationary osteocytes, and bone-destroying osteoclasts,embedded in a mineralized matrix infused with spaces and canals. In thecase of the hallux valgus, a small piece of bone is removed and the bonerealigned to correct the deformity. Tendon and other soft tissuecorrection may also be required in order to assure full correction ismade.

Depending on the type of bunionectomy, fixation may be required.Fixation may be internal, percutaneous or by external means such as acast or splint, surgical shoe, adhesive form or a dressing. In thebunionectomy the fixation is often internal. This is usually done witheither screws or wire. Once the bone is realigned, the wound isirrigated with warm sterile saline and then sutured closed and adressing applied. Recovery varies according to extent of the surgicalprocedure and each individual's rate of healing.

Usual post-operative care consists of rest, elevation, and ice for thefirst 3-5 days. Depending on the procedure performed some walking may bedone in a special shoe during this time. A check-up is performed in theoffice and the bandage is changed. Often subjects will return to workafter 3-7 days, depending on the requirements of the job. Skin usuallyheals in two weeks and at this time the stitches are removed. Bone takes6-8 weeks to heal. Taking X-rays at regular intervals can assess therate of bone healing. Any bunion surgery results in some stiffness.Physical therapy starts at the second or third week to minimize thisstiffness, usually home exercises are sufficient. If these exercises arenot performed, a poor result may occur due to excessive stiffness.Swelling gradually decreases and, at two months, providing sufficienthealing of the bone has occurred, regular shoes may be worn. Regularactivities can often be resumed at two to three months as tolerated.Some swelling may be present for six months or more. The recovery periodvaries according to procedure and each individual's rate of healing.Some factors such as circulation, smoking, bone quality, and generalhealth can also have an effect.

Treatment for pain after bunionectomy surgery typically consists ofopioid and/or NSAIDs/COX-2 inhibitors. In some cases, opioid are givenfor the first 3-5 days and then the subject is treated with an NSAID orCOX-2 Inhibitor. However, interest in the cardiovascular risk associatedwith the use of NSAID/COX-2 inhibitors has become intense, raisingserious questions regarding the use of such agents. It has beendiscovered that an oral administrable composition comprising low dosages(e.g. between about 13 mg to about 30 mg) of diclofenac potassium, in adispersible liquid formulation (relative to conventional dosage amountsof 50 mg or more) is surprisingly effective in providing immediateeffective relief of moderate to severe acute pain to patients followingpost-surgical procedures, particularly outpatient post-surgicalprocedures such as bunionectomy, such that the need for opioids can bedelayed, reduced or eliminated altogether. Furthermore, the reduction ofthe unit dosage amount of diclofenac potassium can lead to a substantialreduction or elimination of the risk of a cardiovascular event.

The term “acute pain” as used herein means pain that has a sudden onsetand commonly declines over a short time (days hours, minutes) andfollows injury to the body and which generally disappears when thebodily injury heals. The intensity of the acute pain following abunionectomy can be mild to moderate, moderate to moderately severe, ormoderate to severe.

Pain rating scales are used in daily clinical practice to measure painintensity. The commonly used measurement scales include the VisualAnalog Scale (VAS), the Graphic Rating Scale (GRS), the SimpleDescriptor Scale (SDS), the Numerical Rating Scale (NRS), and the FacesRating Scale (FRS). All of these scales have been documented as beingvalid measures of pain intensity. The three scales most commonly used inthe U.S. are the numerical, word and faces scales.

The visual analog scale (VAS) is a 10 cm. vertical or horizontal linewith word anchors at the extremes, such as “no pain” on one end and“pain as bad as it could be” at the other. The patient is asked to makea mark along the line to represent pain intensity.

The graphic rating scale (GRS) is a variation of the visual scale whichadds words or numbers between the extremes. Wording added might include“no pain”, “mild”, “severe”.

The descriptor scale (SDS) is a list of adjectives describing differentlevels of pain intensity. For example pain intensity may be described as“no pain”, “mild”, “moderate” or “severe”.

The numerical pain rating scale (NPRS) refers to a numerical rating of 0to 10 or 0 to 5 or to a visual scale with both words and numbers. Thepatient is asked to rate the pain with 0 being no pain and 10 being theworst possible pain. The faces scale was developed for use withchildren. This scale exists in several variations but relies on a seriesof facial expressions to convey pain intensity.

Grouping patients' rating of pain intensity as measured with a numericalscale ranging from 0 to 10 into categories of mild, moderate, and severepain is useful for informing treatment decisions, and interpreting studyoutcomes. In 1995, Serlin and colleagues (Pain, 1995, 277-84) developeda technique to establish the cut points for mild, moderate, and severepain by grading pain intensity and functional inference. Since then, anumber of studies have been conducted to correlate the numerical scales,for example the NPRS, with cutpoints related to levels of painintensity. Common severity cutpoints are (1 to 4) for mild pain, (5 to6) for moderate pain, and (7 to 10) for severe pain.

The term “patient” as used herein refers to a warm blooded animal suchas a mammal which is the subject of surgical trauma. It is understoodthat at least dogs, cats, mice and humans are within the scope of themeaning of the term.

As used herein, the term “treatment”, or a derivative thereof,contemplates partial or complete inhibition of acute pain, when acomposition of the present invention is administered following the onsetof acute pain.

In one embodiment, a method is provided for treatment of acute painfollowing a post-surgical procedure, particularly following an osteotomysuch as a bunionectomy. The method comprising orally administering tothe patient between about 13 to about 30 mg, usually about 13 mg, 13.5mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 28 mg or 30mg of diclofenac potassium in a dispersible liquid formulation. Suitableoral dispersible liquid formulations are described, for instance, inU.S. Pat. Nos. 5,183,829 and 6,365,180, which is incorporated byreference in its entirety.

The diclofenac potassium in the dispersible liquid formulation can beadministered about every 4 hours to 8 hours for a period of at leastabout 24 hours, at least about 36 hours, at least about 48 hours, atleast about 72 hours, at least about 96 hours, at least about 120 hours,or at least about 144 hours or at least about seven (7) days, whereinthe daily total amount of diclofenac potassium administered is less thanor equal to about 100 mg.

In a specific embodiment, a dosage amount of about 25 mg diclofenacpotassium in a dispersible liquid formulation has been found to besuitable for treating acute pain, e.g., mild to moderate, moderate tomoderately severe, or moderate to severe, resulting from post-surgicaltrauma, e.g., such as that resulting from an osteotomy. A dosage amountof 25 mg diclofenac has been found to be particularly effectively fortreating post-bunionectomy acute pain.

In a specific embodiment, diclofenac potassium salt in a dispersibleliquid formulation in the dosage amounts discussed above can beadministered at an interval of at least about 4 hours, at least about 5hours, at least about 6 hours, or at least about 8 hours. Theadministered amount of diclofenac potassium salt can be effective inproviding acute pain relief for about 4 to about 8 hours, preferentiallyfor about 6 to about 8 hours, after administration.

In a specific embodiment, the method of the invention utilizes about 25mg of diclofenac potassium contained in a dispersible liquid formulationcontained in a liquid-filled, soft gelatin capsule. The formulationincludes a combination of polyethylene glycol 400, glycerin, sorbitol,povidone, polysorbate 80, and hydrochloric acid, isopropyl alcohol, andmineral oil.

In a specific embodiment, the diclofenac potassium composition useful inthe inventive method can provide a plasma concentration of diclofenac ina patient ranges between about 670 to about 1500 ng/ml in less than 30minutes with the concomitant onset of relief of acute pain.

In a specific embodiment, the administration of diclofenac potassiumcomposition in accordance with the inventive method can result inimmediate increase in plasma concentration of diclofenac characterizedby T(max) of about 0.47.

In a specific embodiment, the diclofenac potassium composition useful inthe method of the invention provides the following mean pharmacokineticcharacteristics of: a terminal half-life (hr) of 1.07+0.29; a Cmax(ng/mL) of 1087+419; and an AUC (0 to infinity) (ng.h/mL) of 597+151.

In another embodiment, diclofenac is substantially eliminated fromplasma in the first 2 hours following administration. As defined herein,the phrase “substantially eliminated” means at least about 75%, 80%,85%, 90% or 95% of diclofenac is eliminated from plasma in the first 2hours or after about the first 2 to 3 hours.

The following examples provide a representative composition comprisingdiclofenac potassium in a dispersible liquid formulation (Example 1) andmethod of treating post-bunionectomy acute pain using diclofenacpotassium in a dispersible liquid formulation (Example 2). Thematerials, methods, and examples herein are illustrative only and,except as specifically stated, are not intended to be limiting.

EXAMPLES Example 1 Preparation of Liquid Diclofenac PotassiumFormulation

A typical formulation used in pain treatment is summarized in Table 1

TABLE 1 Ingredient Description A % w/w B % w/w C % w/w Diclofenac Active6.25 6.25 6.25 Potassium (25 mg) PEG 400 NF Dispersing agent; 70.1269.70 66.95 Solubilizing agent Glycerin Co-solvent; 10.0 10.0 10.0Plasticizing agent Sorbitol Solubilizing 5.0 5.0 5.0 Solution agent;Stabilizing 70% agent; Plasticizing agent Povidone USP Dispersing agent;6.3 6.3 6.3 (PVP K-30) Polysorbate 80 Emulsifying 1.5 1.5 3.0 agent;Surfactant 6N HCl Softgel 0.83² 1.25 NA Stabilizing agent 2N HCl SoftgelNA NA 2.5 Stabilizing agent Nitrogen Gas (if Overlay Overlay Overlaystored prior to filling)

PEG 400 was heated to about 45° C. in a cowls mixer. One half ofPolysorbate 80 was then added to the heated PEG 400 and mixed whilemaintaining the temperature at about 45° C. Diclofenac potassium wasthen added and mixed to dissolve while maintaining the temperature,followed by addition of Povidone to the mixture. The contents were mixedto dissolve new additions at each step while maintaining the temperatureat 45° C. The mixture was cooled to about 25-30° C. while continuing tomix. 6N HCL subsequently added and mixed followed by mixing remainingPolysorbate 80 into the mixture. Glycerin and Sorbitol were then addedand mixed while continuing to maintain the temperature at about 25-30°C. The final pH to about 6. The solution was filtered and filled into 25mg soft gelatin capsules (400 mg fill weight).

Example 2 Method for Treatment of Post-Surgical Acute Pain Using LiquidDiclofenac Potassium Formulation

Clinical studies were conducted to determine the analgesic efficacy ofDiclofenac Potassium Soft Gelatin Capsules (DPSGC) 25 mg in acutesurgical pain. The study was a placebo controlled study in subjectsrecovering from bunionectomy surgery. A total of 201 subjects, 102 inthe DPSCG group and 99 in the placebo group, were enrolled, randomizedand received at least one dose of study drug. Three subjects, 1 in theDPSCG and 2 in the placebo group discontinued.

The primary efficacy variable was the average pain intensity over a48-hour multiple dose period calculated using an 11-point Numerical PainRating Scale (NPRS).

Other variables analyzed to evaluate analgesic effect of DiclofenacPotassium Soft Gelatin Capsules included:

(1) Evaluation of the analgesic efficacy of a single dose of DPSGC(during the initial dosing period) with individual pain intensityassessments as compared to placebo;

(2) Evaluation of the time needed to re-medication (during the initialdosing period) of a single dose of DPSGC as compared to placebo;

(3) Evaluation evaluate the frequency and timing (defined as time ofmeaningful pain relief) of obtaining clinically significant analgesicefficacy (defined as a 30% reduction in pain intensity) as compared toplacebo in acute pain;

(4) Evaluation of the use of rescue medication during the multiple doseperiod;

(5) Evaluation of the time to onset of obtaining a ≧30% reduction inpain intensity, as compared to placebo, and its duration in acute pain;and

(6) Evaluation of the safety and tolerability of DPSGC 25 mg when usedfor the treatment of acute surgical pain.

The efficacy measures in the study included the NPRS, the Pain ReliefRating Scale, and the Time to Meaningful, Perceptible Pain Relief, and aGlobal Assessment of Study Medication.

Numerical Pain Rating Intensity Scale (NPRS):

The 11-point NPRS was utilized to assess the primary endpoint. At eachtime point, subjects evaluated their current pain intensity relative toan 11-point numerical rating scale. A score of zero represented no painand a score of 10 represented worst possible pain.

Subjects were instructed to: “Rate your pain by recording the one numberthat best describes the amount of pain you have at this time.”

0 1 2 3 4 5 6 7 8 9 10 No Worst Possible Pain Pain

Pain Relief Rating Scale:

Subjects assessed their level of pain relief using a 5-point Pain ReliefRating Scale. A worksheet with a list of adjectives was provided to thesubject, and the subject was asked to respond to the following question:“How much relief do you have from your starting pain?”

0 No pain relief 1 A little pain relief 2 Some pain relief 3 A lot ofpain relief 4 Complete pain reliefTime to Meaningful and Perceptible Pain Relief:

When the subject received study medication, the Study Coordinatorstarted 2 stopwatches and covered the time displays. To determine theexact moment that the subject began to obtain first perceptible relief,the subject was given the stopwatch 3-4 minutes after dosing and wasinstructed as follows: “Stop the stopwatch when you have perceptiblepain relief, that is, when the relief from pain is first noticeable toyou.”

Determination of the exact moment that the subject began to obtainmeaningful relief was attained similarly, except that the question was:“Stop the stopwatch when you have meaningful pain relief, that is, whenthe relief from pain is meaningful to you.”

The elapsed time for each of these determinations was recorded.

Subject Global Assessment of Study Medication:

The subject provided an overall (global) evaluation of the studymedication on a 5-point categorical scale. A worksheet with ratings wasgiven to the subject, and the subject was asked to respond to thefollowing question: “How would you rate this study medication as a painreliever?”

1 Poor

2 Fair

3 Good

4 Very good

5 Excellent

Secondary Efficacy Endpoints

Secondary efficacy endpoints were onset of perceptible and meaningfulpain relief during the single-dose period on Day 1, TOTPAR during thesingle-dose period on Day 1, and onset of 30% reduction from baseline inpain intensity during the single-dose period on Day 1. furtherdescriptions of these endpoints follow.

Onset of perceptible and meaningful pain relief was based on doublestopwatch method and measured on Day 1. Subjects who discontinued thestudy before onset were censored at the time of the last on-study NPRSevaluation. Subjects who received rescue medication or study drugre-medication before onset were censored at the time that rescuemedication or study drug was administered. Total Pain Relief (TOTPAR)was calculated with the trapezoidal rule for the pain relief at 10, 15,20, 30, 45, and 60 minutes and at 1.5, 2, 2.5, 3, 4, 5, 6, 7, and 8hours after the initial dose on Day 1 or until the time ofre-medication. The calculation was similar to that for the SPID(described below). Imputation of missing values before re-medication wasperformed with the WOCF (worst observation carried forward) approach asdefined for the primary efficacy endpoint.

The onset of a ≧30% reduction in pain intensity after the administrationof the first dose of the study drug on Day 1 was measured. Subjects whodiscontinued the study before onset were censored at the time of thelast on-study NPRS evaluation. Subjects who received rescue medicationor study drug re-medication before onset were censored at the time thatrescue medication or study drug was administered.

The sum of Pain Intensity Differences (SPID) over the 48-hour multipledose period was measured. Differences were calculated from the pre-Dose1 pain assessment on Day 1. Imputation of missing scheduled observationsand of pain assessments following rescue medication was performed withthe same method used for the primary efficacy endpoint. Pain assessmentsat the time of rescue medication and scheduled pain assessments (imputedor observed) were included in the calculation. The calculation methodfor the Day 1 SPID (described below) was used.

Sum of Pain Intensity Differences (SPID) was calculated with thetrapezoidal rule for the pain intensity differences at 10, 15, 20, 30,45, and 60 minutes and at 1.5, 2, 2.5, 3, 4, 5, 6, 7, and 8 hours afterthe initial dose on Day 1 or until the time of re-medication. The areabetween 2 consecutive time points was calculated as ([time 2−time1]×[pain intensity difference at time 2+pain intensity difference attime 1])/2. Imputation of missing values before re-medication wasperformed with the WOCF approach as defined for the primary efficacyendpoint.

Pain intensity, pain intensity difference, and pain relief were measuredat 10, 15, 20, 30, 45, and 60 minutes and at 1.5, 2, 2.5, 3, 4, 5, 6, 7,and 8 hours after the initial dose on Day 1 or until the time ofre-medication. Pain intensity was assessed using the NPRS and the painintensity difference was calculated as the change in pain intensity frombaseline to the time point. Pain intensity at pre-Dose 1 was consideredbaseline. Pain relief was assessed using a 5-point relief rating scale(0=no relief, 4=complete pain relief). Imputation of missing valuesbefore re-medication was performed with the WOCF approach as defined forthe primary efficacy endpoint.

Proportion of subjects requiring rescue medication, total number ofrescues on each postoperative day, and quantity of rescue medication oneach postoperative day was measured. Postoperative day was the same ascalendar day. If no rescue medication was required for a subject, thetotal number of rescues and quantity of rescue medication were countedas zero. Otherwise, missing data were not imputed.

Mean rescue interval during the multiple dose period (Days 1-4) wasmeasured. The mean rescue interval was calculated from the rescueintervals during each 6-hour dosing interval for postoperative Days 1-4.The rescue interval was defined as the difference between the dosingtime and either the time that a rescue medication was taken (if any) orthe time of the next study drug administration, whichever was less.

Proportion of subjects discontinuing due to inadequate pain relief, wasrecorded on the Day 5 completion CRF (case report form). This includedsubjects who discontinued due to inadequate pain relief during thesingle-dose portion of the study.

Subjects' global assessment of study drug at discharge and on Day 5 orearly termination was measured.

Time to re-medication following the initial dose on Day 1 was measured.Subjects who discontinued the study before study drug re-medication werecensored at the time of the last on-study NPRS evaluation. Subjects whoreceived rescue medication before study drug re-medication were censoredat the time that rescue medication was administered.

The duration of obtaining a ≧30% reduction in pain intensity after theadministration of the first dose of the study drug on Day 1 wasmeasured.

Proportion of subjects achieving clinically significant analgesicefficacy after the administration of the first dose of the study drug onDay 1 was monitored. Clinically significant analgesic efficacy wasdefined as both ≧30% reduction from baseline pain intensity using NPRSand meaningful relief as indicated by the stopwatch method. The eventsmay have occurred at any time after dosing on Day 1 and the 2 events mayhave occurred at different times on Day 1. Subjects were consideredfailures for this endpoint if they discontinued the study or receivedstudy drug re-medication before the last event occurred.

Proportion of subjects experiencing mild to no pain (NPRS≦2) after theadministration of the first dose of study drug on Day 1. Subjects wereconsidered failures for this endpoint if they discontinued the study,received rescue medication, or received study drug re-medication beforeexperiencing mild to no pain.

SPID and TOTPAR were analyzed with an analysis of covariance or ANCOVAmodel having factors for treatment and site and with the baseline value(pain intensity NPRS Score) as covariate. The 2-way ANOVA with factorsfor treatment and site was used to analyze average rescue interval andduration of a ≧30% reduction in pain intensity. The number of rescues oneach day and the amount of rescue medication on each day were analyzedfor treatment differences with the Wilcoxon test.

The treatment-by-site interaction was assessed in a supportive ANCOVAmodel for the primary endpoint. If the treatment-by-site interaction wasstatistically significant, exploratory data analysis could have beenperformed to provide an adequate description of the interaction. If aquantitative interaction was present, the overall treatment effect wasto be estimated over sites based on the final model with the interactioneffect and all other statistically significant effects. If a qualitativeinteraction was present, the potential cause of the interaction (such assubject characteristics, clinic management, data/CRF handling) was to beexplored.

Least squares means (LS-means) for each treatment, differences in theLS-means between the treatments, and 95% confidence intervals for thetreatment difference in LS-means were also provided for endpointsanalyzed with the 2-way analysis of variance, ANOVA, or analysis ofcovariance, ANCOVA.

Categorical efficacy endpoints were analyzed with theCochran-Mantel-Haenszel test with site as the stratification factor.Endpoints included the proportion of subjects achieving clinicallysignificant analgesic efficacy, proportion of subjects requiring rescuemedication, proportion of subjects discontinuing due to inadequate painrelief, global assessment of study drug, proportion of subjectsachieving no or mild pain, pain intensity at each time point, painintensity difference at each time point, and pain relief at each timepoint.

All time-to-event efficacy endpoints were summarized for each treatmentgroup using Kaplan-Meier survival curves. This method estimated themedian and 95% confidence limits for the time-to-event in each treatmentgroup. Treatment groups were compared using a log-rank test. Inaddition, a Cox proportional hazard model was used with effects fortreatment, baseline pain intensity score (based on the Pain IntensityNPRS score), and any demographic characteristic that was found to bestatistically significantly different between treatment groups (if any)(p≦0.05). The treatment factor was parameterized using reference cellparameterization with placebo as the reference group such that theparameter estimate for the DPSGC 25 mg product represented the adjustedtreatment effect and the Wald Chi-Square statistic provided a test ofthe DPSGC 25 mg product vs. placebo effect.

Treatment Regimen:

This was a multicenter, randomized, double-blind, parallel-group,placebo-controlled study in subjects recovering from bunionectomysurgery. The study consisted of 2 dosing periods: an initial dosingperiod (on Day 1) followed by a multiple dose period (through Day 4).

Subjects were provided 1-2 tablets of hydrocodone/acetaminophen (APAP)(5 mg/500 mg) every 4 to 6 hours as needed for pain, not to exceed 8tablets daily during the day of surgery and up until 4 hours before thetreatment study began. Analgesic use was recorded. If subjects requiredpain medication other than that specified per protocol, they werediscontinued. The use of ice packs was allowed on Day 0 and on Day 1 upto 3 hours after the last analgesic dose taken prior to randomization(study medication dose 1) but not after randomization during Days 1-4.

Upon awakening at 4 am or later on the morning of Day 1 (initial dosingperiod), subjects who complained of having increased pain assessed theirpain intensity at rest (no activity of the affected toe for at least 10minutes prior to pain assessments) using the 11-point NPRS (0=no pain,10=worst pain imaginable). When subjects first reported a pain intensityscore of at least 4 between 4 am and 10 am, they were randomly allocatedto 1 of 2 blinded treatment arms: Arm A (placebo) or Arm B (25 mgDPSGC). All pain medication (i.e., hydrocodone/APAP) was to have beendiscontinued at least 4 hours before the initial dose of studymedication.

After taking the first dose, subjects were provided 2 stopwatches torecord the time to onset of perceptible pain relief and the time toonset of meaningful pain relief. Pain intensity and pain reliefassessments and vital signs were measured at various time points afterthe initial dose or until the time of re-medication.

The second dose (re-medication) was given to the subject when thesubject requested the second dose to treat his/her pain. If the subjectdid not indicate a need for re-medication within 8 hours of taking thefirst dose of study medication, he/she was given the second dose ofstudy medication at 8 hours.

The re-medication dose was the second dose of the study and marked thestart of the 48-hour assessment period, during which subjects took theirstudy medication every 6 hours. Following the re-medication dose,subsequent doses while in the study unit occurred every 6 hours (+/−1hour from the 6-hour schedule established at the time of re-medication).Study medication use was not to exceed 4 doses in one 24-hour period.Subjects were discharged after the 48-hour period was completed and wereinstructed to take their medication on an outpatient basis at 6 am, 12pm, 6 pm and 12 am. The last dose of study medication was taken at 12midnight on Day 4.

Rescue medication consisting of hydrocodone/APAP (5 mg/500 mg) wasavailable for the subjects after the re-medication dose. However,subjects were encouraged to delay taking rescue medication until atleast 1 hour after receiving study medication. Subjects who took rescuemedication recorded a pain assessment at the time of rescue and took thesubsequent doses of study medication on schedule. They continued theremaining pain assessments.

The primary efficacy endpoint of the average of pain intensity over 48hours was analyzed using an analysis of covariance (ANCOVA) model withfactors for treatment and site and baseline pain intensity score (usingthe pain intensity NPRS Score; 0=no pain, 10=worst pain imaginable) as acovariate.

SPID and TOTPAR were analyzed with an ANCOVA model having factors fortreatment and site and with the baseline value (pain intensity NPRSScore) as covariate. The 2-way analysis of variance (ANOVA) with factorsfor treatment and site was used to analyze average rescue interval andduration of a ≧30% reduction from baseline in pain intensity. The numberof rescues on each day and the amount of rescue medication on each daywere analyzed for treatment differences with the Wilcoxon test. Thetreatment-by-site interaction was assessed in a supportive ANCOVA modelfor the primary endpoint. Least squares means (LS-means) for eachtreatment, differences in the LS-means between the treatments, and 95%confidence intervals for the treatment difference in LS-means were alsoprovided for endpoints analyzed with the 2-way ANOVA or ANCOVA.

Categorical efficacy endpoints were analyzed with theCochran-Mantel-Haenszel test with site as the stratification factor. Alltime-to-event efficacy endpoints were summarized for each treatmentgroup using Kaplan-Meier survival curves. In addition, a Coxproportional hazard model was used with effects for treatment andbaseline pain intensity score (based on the Pain Intensity NPRS Score).Pain measures taken after re-medication or use of rescue medication wereconsidered missing and replaced using worst observation carried forward(WOCF) methodology.

Evaluation of Efficacy of Analgesic Effect of Liquid Formulation ofDiclofenac Potassium:

The primary efficacy assessment endpoint was the average pain intensityover the 48-hour multiple dose period. Pain intensity was measured usinga NPRS of 0 to 10 (0=no pain, 10=worst possible pain).

All observed, scheduled NPRS pain assessments were averaged for eachsubject over the 48-hour multiple dose period, unless rescue medicationwas administered. If rescue medication was administered, scheduled painassessments were considered missing for 6 hours following administrationof rescue medication and the pain assessment at the time of rescuemedication was carried forward. If rescue medication was administeredmore than once within 6 hours, the pain assessment at the first rescuewas carried forward until there had been at least 6 hours since the useof last rescue. Pain assessments at the time of rescue medication andscheduled pain assessments (imputed or observed) were included in theaverage pain intensity over the 48-hour multiple dose period. Missingscheduled pain assessments for subjects who did not prematurelydiscontinue from the study were imputed with the worst observationcarried forward (whether it was the baseline or some other value) up tothe time of the missing observation (regardless of whether the worstvalue occurred in association with rescue medication). For subjects whoprematurely discontinued from the study, the worst observation (whetherit was the baseline or some other value) was carried forward for theremainder of the 48-hour multiple dose period (regardless of whether theworst value occurred in association with rescue medication).

The primary efficacy endpoint of the average of pain intensity over 48hours was analyzed using an ANCOVA model with factors for treatment andsite and baseline pain intensity score (using the pain intensity NPRSScore) as a covariate. The baseline pain intensity score was the lastpain intensity score obtained before study drug dosing on Day 1.

The 3-hour post-dose pain assessment was not required if it fell betweenmidnight and 5 am. If these values were not obtained, they were notconsidered missing data points and were not imputed.

Subjects recorded their pain intensity post-operatively on a 0-10numerical pain rating scale (NPRS). A clinically significant differencewas felt to be 1.5 units on the NPRS for the average pain intensity over48 hours with the NPRS. If the common standard deviation was 3.0, then asample size of 86 subjects per group would provide over 90% power todetect as significant a difference of 1.5 units between the placebo andactive groups using a two-sample t-test with a significance level of0.05 two-sided.

No statistically significant difference was observed between the DPSGC25 mg and placebo groups for the mean NPRS pain intensity score atbaseline (6.89 and 7.29, respectively). The difference between thetreatment groups in average pain intensity over the 48-hour multipledose period, calculated using the 11-point NPRS, was statisticallysignificant in the full analysis population (Table 2).

TABLE 2 Primary Endpoint Placebo DPSGC 25 mg p-value Average 48-HourPain Intensity 5.56 2.49 <0.0001 NPRS Score

In the full analysis population, the difference between the treatmentgroups in average pain intensity over the 48-hour multiple dose period,calculated using the 11-point NPRS was statistically significant usingthe WOCF methodology (p<0.0001). A lower average pain score was observedin the DPSGC 25 mg group compared to the placebo group (2.49 vs. 5.56).This substantial difference (greater than 2 points) in average painintensity would be expected to provide a significant clinical benefit tosubjects. Results were similar in the evaluable population and when LOCF(last observation carried forward) and observed cases methodologies wereused. A summary of average pain intensity over the 48-hour multiple doseperiod for the full analysis and evaluable populations is presented inTable 3.

TABLE 3 Average 48-Hour Pain Intensity NPRS Score During Multiple DosePeriod (Full Analysis and Evaluable Populations) Population (ImputationMethod) Placebo DPSGC 25 mg p-value^(a) Full Analysis (WOCF) (N = 99) (N= 102) <0.0001 Mean (SD) 5.56 (2.026) 2.49 (1.967) Median 5.65 1.85Min-Max 0.50-10.00 0.00-7.83 LS-mean 5.60 2.71 Difference in LS-means2.89 95% CI for difference 2.43, 3.35 in LS-means Evaluable (WOCF) (N =95) (N = 96) <0.0001 Mean (SD) 5.44 (1.950) 2.39 (1.926) Median 5.531.76 Min-Max 0.50-9.58 0.00-7.83 LS-mean 5.50 2.56 Difference inLS-means 2.94 95% CI for difference in 2.48, 3.39 LS-means WOCF = worstobservation carried forward; SD = standard deviation; Min = minimum; Max= maximum; LS-mean = least squares means ^(a)From ANCOVA with factorsfor treatment and site, and with baseline pain intensity as covariate.

No statistically significant interactions of treatment with study siteand baseline pain severity were observed. All of the factors werestatistically significant in the model.

Results for the secondary endpoints in the full analysis population forboth the 48-hour multiple dose and 8-hour initial dosing periods aresummarized in Table 4.

TABLE 4 Secondary Endpoints in Inpatient DPSGC p- 48-Hour Multiple DosePeriod Placebo 25 mg value Mean SPID 90.26 210.01 <0.0001 Mean peak PID5.47 6.44 <0.0001 Mean rescue interval (minutes) 263.88 331.54 <0.0001Rescue use Proportion of subjects on Day 1 87.9% 39.2% <0.0001Proportion of subjects on Day 2 64.6% 21.6% <0.0001 Proportion ofsubjects on Day 3 29.3% 4.9% <0.0001 (up to discharge) Subject's globalassessment at n (%) n (%) discharge Poor 25 (25.3%) 1 (1.0%) Fair Good15 (15.2%) 6 (5.9%) 24 (24.2%) 14 (13.7%) Very Good 19 (19.2%) 28(27.5%) Excellent 15 (15.2%   52 (51.0%) Mean response 2.84 4.23 <0.0001

TABLE 5 Secondary Endpoints in Inpatient 8-Hour Initial Dosing PeriodPlacebo DPSGC 25 mg p-value Mean SPID 4.06 11.67 <0.0001 Peak painrelief 1.44 2.19 0.0006 Mean TOTPAR 2.63 8.16 <0.0001 Proportion ofsubjects achieving perceptible pain relief 69.7% 82.4% 0.0380 Medianonset to perceptible pain relief (minutes) 22.18 26.01 0.2348 Proportionof subjects achieving meaningful pain relief 35.4% 56.9% 0.0025 Medianonset to meaningful pain relief (minutes) 106.30 70.22 0.0080 Mediantime to re-medication (minutes) 80.00 156.50 <0.0001 Proportion ofsubjects achieving ≧ 30% reduction in pain 40.4% 60.8% 0.0043 Mediantime to onset of ≧ 30% reduction in pain (minutes) 150 60 0.0376 Meanduration of ≧ 30% reduction in pain (minutes) 134.08 241.44 0.0132Proportion of subjects achieving clinically significant analgesic 29.3%52.9% 0.0008 efficacy after first dose Proportion of subjectsexperiencing mild to no pain after first dose 23.2% 44.1% 0.0019Estimated using Kaplan-Meier product limit estimates.Mean Rescue Interval

Mean interval between protocol-scheduled study drug dosing andadministration of rescue medication or the next protocol-scheduled studydrug dose (whichever occurred first) during the 48-hour multiple doseperiod was statistically significantly (p<0.0001) longer in the DPSGC 25mg group compared to the placebo group, 331.54 vs. 263.88 minutes.Similarly, the mean intervals between dosing and administration ofrescue on Day 1, Day 2, and Day 3 (up to discharge) were statisticallysignificantly (p<0.0001) longer in the DPSGC 25 mg group compared to theplacebo group

The mean interval between dosing and rescue medication lengthened fromDay 1 to Day 3 as would be expected, given the natural waning of painover time after surgery, 308.95 to 350.03 minutes in the DPSGC 25 mggroup; 201.55 to 315.66 minutes in the placebo group. The largestincrease in the mean interval between dosing and rescue medicationoccurred between Dose 2 and Dose 3 in both study groups.

Generally, the average time to rescue in the DPSGC 25 mg group was 5.5to 6 hours, supporting that a 6-hour dosing interval is appropriate.Results were similar in the evaluable population.

A summary of mean interval between dosing and administration of rescueduring the 48-hour multiple dose period for the full analysis andevaluable populations is presented in Table 6.

TABLE 6 Overall Mean Interval Between Dosing and Administration ofRescue During the 48-Hour Multiple Dose Period (Full Analysis andEvaluable Populations) Overall Mean Rescue Interval (minutes)_(a)Placebo DPSGC 25 mg p-value_(b) Full Analysis (N = 99) (N = 102) <0.0001Population Mean (SD) 263.88 (72.461) 331.54 (45.181) Median 271.88354.19 Min-Max 11.0-364.38 152.50-365.63 LS-mean 258.77 325.77Difference in LS- −67.00 means 95% CI for difference −82.38, −51.6 inLS-means Evaluable Population (N = 95) (N = 96) <0.0001 Mean (SD) 269.40(65.523) 332.62 (45.351) Median 283.75 354.38 Min-Max 104.38-364.38152.50-365.63 LS-mean 263.95 327.53 Difference in LS- −63.58 means 95%CI for difference −78.48, −48.6 in LS-means SD = standard deviation; Min= minimum; Max = maximum; LS-mean = least squares mean a Mean rescueinterval was defined as the interval between protocol-scheduled studydrug dosing and administration of rescue medication or the nextprotocol-scheduled study drug dose (whichever occurred first). Duringthe inpatient period, a statistically significantly smaller proportionof subjects in the DPSGC 25 mg group compared to the placebo group usedrescue medication on Day 1, Day 2, and up to discharge on Day 3.

During the inpatient period, a statistically significantly smallerproportion of subjects in the DPSGC 25 mg group compared to the placebogroup used rescue medication on Day 1, Day 2, and up to discharge on Day3. See Tables 4, 5 and 7 (see Rescue Use).

TABLE 7 Summary of Rescue Medication Use During the 48-Hour MultipleDose Period (Full Analysis and Evaluable Populations) Placebo DPSGC 25mg Day 3 Day 3 (up to (up to Variable Day 1 Day 2 discharge) Day 1 Day 2discharge) Full Analysis Population (N = 99) (N = 102) Rescue MedicationUse, n (%) 87 64 29 40 22 5 (87.9%) (64.6%) (29.3%) (39.2%) (21.6%)(4.9%) p-value vs. placebo_(a) <0.0001 <0.0001 <0.0001 Number ofAdministrations (among users of rescue medications) Mean (SD) 2.37 2.171.07 1.93 2.09 1.00 (1.221) (1.121) (0.258) (1.047) (1.269) (0.000)Median 2.00 2.00 1.00 2.00 2.00 1.00 Min-Max 1-5 1-5 1-2 1-4 1-5 1-1p-value vs. placebo_(b) 0.0497 0.7782 0.5591 Amount of Rescue Medication(Tablets) (among users of rescue medications) Mean (SD) 3.78 3.28 1.623.03 2.95 1.40 (2.020) (1.804) (0.677) (2.106) (1.889) (0.548) Median4.00 3.00 2.00 2.00 2.50 1.00 Min-Max 1-8 1-10 1-4 1-8 1-8 1-2 p-valuevs. placebo_(b) 0.0553 0.4710 0.4962 Evaluable Population (N = 95) (N =96) Rescue Medication Use, n (%) 83 (87.4%) 62 (65.3%) 28 (29.50%) 36(37.5%) 20 (20.8%) 5(5.2%) p-value vs. placebo_(a) <0.0001 <0.0001<0.0001 Number of Administrations (among users of rescue medications)Mean (SD) 2.39 2.18 1.07 1.97 2.10 1.00 (1.218) (1.138) (0.262) (1.055)(1.334) (0.000) Median 2.00 2.00 1.00 2.00 2.00 1.00 Min-Max 1-5 1-5 1-21-4 1-5 1-1 p-value vs. placebo_(b) 0.0797 0.8005 0.5522 Amount ofRescue Medication (Tablets) (among users of rescue medications) Mean(SD) 3.77 3.27 1.61 3.14 3.00 1.40 (1.996) (1.830) (0.685) (2.180)(1.974) (0.548) Median 4.00 3.00 2.00 2.00 2.50 1.00 Min-Max 1-8 1-101-4 1-8 1-8 1-2 p-value vs. placebo_(b) 0.1255 0.5692 0.5284 SD =standard deviation; Min = minimum; Max = maximum _(a)From Cochran MantelHaenszel test with site as strata. _(b)From ANOVA with factors forpoolsite and treatment.

Among subjects who used rescue medication, the mean number of rescuemedication administrations and mean amount of rescue medication weresmaller in the DPSGC 25 mg group compared to the placebo group on Day 1,Day 2, and Day 3 (up to discharge); a statistically significanttreatment difference occurred on Day 1 for number of administrations.See Table 7.

Use of and Amount of Rescue Medication after Discharge

After discharge on Day 3 during the outpatient period, a statisticallysignificantly smaller proportion of subjects in the DPSGC 25 mg groupcompared to the placebo group used rescue medication on Day 3 (12.7% vs.39.4%; p<0.0001) and on Day 4 (9.8% vs. 38.4%; p<0.0001) in the fullanalysis population. Results were similar in the evaluable population.

A summary of rescue medication use after discharge on Day 3 during theoutpatient period for the full analysis and evaluable populations ispresented in Table 8.

TABLE 8 Summary of Rescue Medication Use After Discharge on Day 3 Duringthe Outpatient Period (Full Analysis and Evaluable Populations) VariablePlacebo DPSGC 25 mg Day 3 Day 3 (after (after discharge) Day 4 Day 5discharge) Day 4 Day 5 Full Analysis Population (N = 99) (N = 102)Rescue Medication Use, n (%) 39 38 9 13 10 7 (39.4%) (38.4%) (9.1%)(12.7%) 10 (9.8%) (6.9%) p-value vs. placebo_(a) <0.0001 <0.0001 0.5502Number of Administrations (among users of rescue medications) Mean (SD)1.46 1.92 1.44 1.62 2.30 1.57 (0.643) (1.075) (1.014) (0.650) (1.160)(1.134) Median 1.00 2.00 1.00 2.00 2.00 1.00 Min-Max 1-3 1-4 1-4 1-3 1-41-4 p-value vs. placebo_(b) 0.4595 0.3340 0.8167 Amount of RescueMedication (Tablets) (among users of rescue medications) Mean (SD) 1.852.39 1.67 2.00 2.30 1.57 (1.182) (1.264) (1.000) (1.000) (1.160) (1.134)Median 1.00 2.00 1.00 2.00 2.00 1.00 Min-Max 1-6 1-4 1-4 1-4 1-4 1-4p-value vs. placebo_(b) 0.6755 0.8313 0.8610 Evaluable Population (N =91) (N = 96) Rescue Medication Use, n (%) 35 36 9 12 9 6 (38.5%) (39.6%)(9.9%) (12.5%) (9.4%) (6.3%) p-value vs. placebo_(a) <0.0001 <0.00010.3856 Number of Administrations (among users of rescue medications)Mean (SD) 1.46 1.94 1.44 1.67 2.44 1.67 (0.657) (1.094) (1.014) (0.651)(1.130) (1.211) Median 1.00 2.00 1.00 2.00 2.00 1.00 Mm-Max 1-3 1-4 1-41-3 1-4 1-4 p-value vs. placebo_(b) 0.3446 0.2296 0.7061 Amount ofRescue Medication (Tablets) (among users of rescue medications) Mean(SD) 1.86 2.44 1.67 2.00 2.44 1.67 (1.216) (1.275) (1.000) (1.044)(1.130) (1.211) Median 1.00 2.00 1.00 2.00 2.00 1.00 Min-Max 1-6 1-4 1-41-4 1-4 1-4 p-value vs. placebo_(b) 0.7183 1.0000 1.0000 SD = standarddeviation; Min = minimum; Max = maximum _(a)From Cochran Mantel Haenszeltest with site as strata. _(b)From ANOVA with factors for poolsite andtreatment.Sum of Pain Intensity Difference

Sum of Pain Intensity Difference (SPID) was calculated with thetrapezoidal rule for the pain intensity differences at 10, 15, 20, 30,45, and 60 minutes and at 1.5, 2, 2.5, 3, 4, 5, 6, 7, and 8 hours afterthe initial dose on Day 1 or until the time of re-medication. The areabetween 2 consecutive time points was calculated as ([time 2−time1]×[pain intensity difference at time 2+pain intensity difference attime 1])/2.

Mean SPID at 8 hours post-dose was statistically significantly(p<0.0001) greater in the DPSGC25 mg group compared to the placebo group(11.67 vs. 4.06). Results were similar in the evaluable population Table9.

A summary of SPID scores at 8 hours post initial dose of study drug forthe full analysis and evaluable populations is presented in Table 9.

TABLE 9 SPID Scores at 8 Hours Post Initial Dose of Study Drug (FullAnalysis and Evaluable Populations) Placebo DPSGC 25 mg p-value_(a) FullAnalysis Population (N = 99) (N = 102) <0.0001 Mean (SD) 4.06 (7.286)11.67 (14.302) Median 0.86 3.28 Min-Max −2.99-38.72 −5.24-50.69 LS-mean3.83 11.40 Difference in LS-means −7.57 95% CI for difference in LS-−10.75, −4.38 means Evaluable Population (N = 95) (N = 96) <0.0001 Mean(SD) 4.20 (7.404) 12.32 (14.457) Median 0.86 4.58 Min-Max −2.99-38.72−2.33-50.69 LS-mean 3.96 12.12 Difference in LS-means −8.16 95% CI fordifference in LS- −11.45, −4.87 means SD = standard deviation; Min =minimum; Max = maximum; LS-mean = least squares mean _(a)From 2-wayANOVA with factors for treatment and site.

During the initial dosing period, mean pain intensity scores werestatistically significantly lower in the DPSGC 25 mg group compared tothe placebo group at 1 hour (p=0.0470) and from 2 hours through 8 hourspost-dose (p-values ranging from 0.0001 to 0.0091) using WOCFmethodology. Results for PID and pain relief were consistent with thosefor pain intensity scores.

Results from the outpatient multiple dose period followed a similarpattern to those observed in the inpatient 48-hour multiple dose and8-hour initial dosing periods. After discharge on Day 3, a statisticallysignificantly (p<0.0001) smaller proportion of subjects in the DPSGC 25mg group compared to the placebo group used rescue medication on Day 3(12.7% vs. 39.4%) and on Day 4 (9.8% vs. 38.4%).

A statistically significant (p<0.0001) difference between the treatmentgroups was observed for subject's global assessment of study medicationat study completion. Greater percentages of subjects in the DPSGC 25 mggroup compared to the placebo group assessed study drug as very good orexcellent at study completion (79.4% vs. 33.3%). See Table 10. Resultswere similar in the evaluable population. No DPSGC 25 mg subjects andone (1.0%) placebo subject discontinued due to inadequate pain relief.

A summary of subject global assessment of study drug at study completionfor the full analysis and evaluable populations is presented in Table10.

TABLE 10 Subject Global Assessment of Study Drug at Study Completion(Full Analysis and Evaluable Populations) Placebo DPSGC 25 mgp-value_(a) Full Analysis Population (N = 99) (N = 102) Assessment atStudy Completion Poor, n (%) 29 (29.3%)  5 (4.9%) Fair, n (%) 12 (12.1%) 3 (2.9%) Good, n (%) 24 (24.2%) 12 (11.8%) Very Good, n (%) 19 (19.2%)20 (19.6%) Excellent, n (%) Mean 14 (14.1%) 2.77 61 (59.8%) 4.28 <0.0001Response Evaluable Population (N = 95) (N = 96) Assessment at StudyCompletion Poor, n (%) 27 (28.4%)  5 (5.2%) Fair, n (%) 12 (12.6%)  3(3.1%) Good, n (%) 23 (24.2%) 11 (11.5%) Very Good, n (%) 19 (20.0%) 18(18.8%) Excellent, n (%) Mean 14 (14.7%) 2.80 59 (61.5%) 4.28 <0.0001Response SD = standard deviation; Min = minimum; Max = maximum; CI =confidence interval _(a)From Cochran-Mantel-Haenszel test with site asstratification factor.Pain Intensity Over Time

Mean NPRS scores over time during the 48-hour multiple dose period arepresented graphically in FIG. 1. These results show similar levels ofpain intensity at baseline in both groups. At the start of the 48-hourmultiple dose period, which follows the variable-length single-doseportion of the study, the groups are statistically significantlydifferent at all measurement time points (p<0.0001) including thebaseline of the 48-hour multiple dose period (pre-dose 2 pain intensityassessment). This is true for both the measures taken 3 hours followingthe dose and 6 hours following the dose (i.e., at the time of the nextdose). The results at 3 hours post-dose indicate superior analgesicefficacy of DPSGC 25 mg, and the results at 6 hours post-dose indicatethat the analgesia in the DPSGC 25 mg group lasts for the 6-hour dosinginterval. Results were similar in the evaluable population.

No statistically significant difference was observed between the DPSGC25 mg and placebo groups for the mean NPRS pain intensity score atbaseline (6.89 and 7.29, respectively) FIG. 2 shows the mean PID scoresover time. The maximum pain intensity improvement occurred in bothtreatment groups at 45-60 minutes. However, the maximum mean PID wasconsiderably greater in the DPSGC 25 mg group compared to placebo. Thislevel of difference between groups was apparent throughout the follow-upinterval.

Mean PID increased in the placebo group during the first 45 minutespost-dose (0.44 to 1.40). Mean PID increased in the DPSGC 25 mg groupduring the first hour post-dose (0.24 to 2.07) and remained stable from1-2 hours (2.07 to 2.02). The relative difference between the treatmentgroups was generally maintained for the rest of the 8-hour period.

At 2.5 hours post-dose (p=0.0474) and from 4 hours through 8 hourspost-dose on Day 1, mean PID was statistically significantly higher inthe DPSGC 25 mg group compared to the placebo group (with p-valuesranging from 0.0057 to 0.0173). Mean PID scores over time are displayedgraphically in FIG. 2.

Time to Onset of Perceptible and Meaningful Pain Relief

Following the first dose of study medication, subjects were instructedto stop a stopwatch when “you have perceptible pain relief, that is whenthe relief from pain was first noticeable to you,” with similarinstruction for reporting meaningful pain relief. Subjects were allowedto re-medicate as needed, though they were encouraged to wait one hourbefore doing so. For these analyses, subjects were censored at the timeof re-medication. This has the potential to confound the interpretationof the time-to-event analyses, as reporting of perceptible or meaningfulpain relief is related to the need to re-medicate, and could constituteinformed censoring. Since the number of placebo subjects re-medicatingis greater than the number of DPSGC 25 mg subjects, these analyses arelikely to be biased in favor of placebo.

Statistically significantly more subjects in the DPSGC 25 mg group thanin the placebo group reported perceptible pain relief following thefirst dose of study medication: 82.4% vs. 69.7% (p=0.0380), Table 5.Median time to onset of perceptible pain relief (Kaplan-Meier productestimate) was 26.01 minutes in the DPSGC 25 mg group and 22.18 minutesin the placebo group. These median times to onset were not statisticallysignificantly different (overlapping 95% CIs). Similarly, the analysescomparing the full time-to-event curves also found no differencesbetween the groups (log rank p=0.2348 and Wald chi-square p=0.3571).This endpoint arguably is most likely to reflect placebo response of allof the endpoints, given that it reflects an early impression of painrelief, rather than significant and durable relief. The significantimpact of placebo response in pain models is well-documented in theliterature and has been reported for many years. As expected, a largenumber of subjects in both groups were censored at 1 hour due tore-medication, though the number was larger in the placebo group.

Statistically significantly more subjects in the DPSGC 25 mg group thanin the placebo group experienced meaningful pain relief (56.9% vs.35.4%) (p=0.0025), Table 5. The median time to onset of meaningful painrelief after dose 1 (Kaplan-Meier product estimate) was shorter in theDPSGC 25 mg group compared to the placebo group (70.22 vs. 106.30minutes), Table 5. The extended time to meaningful pain relief in thismodel, where baseline pain is severe, could be attributed to the factthat larger changes in pain intensity are necessary to achieve similardegrees of pain relief than when baseline pain is moderate.25 The 95%CIs about the medians overlapped slightly (84.7-not calculable vs.61.2-92.0 minutes), indicating that the difference between the medianswas not statistically significant. However, both the log-rank test andthe Wald chi-square from the Cox proportional hazards model, whichevaluate the entire time-to curve rather than just the medians, indicatea significant difference between the DPSGC 25 mg and placebo groups intime to onset of meaningful pain relief (p=0.0080 for the log-rank testand p=0.0142 for the Wald chi-square). A summary of onset of perceptibleand meaningful pain relief for the full analysis and the evaluablepopulation is presented in Table 11.

TABLE 11 Time to Onset of Perceptible and Meaningful Pain Relief (FullAnalysis and Evaluable Populations) Wald Log-rank Chi-square PlaceboDPSGC 25 mg p-value_(a) p-value_(a) Full Analysis Population Time toperceptible pain relief (N = 99) (N = 102) Subjects with relief, n (%) 69 (69.7%)  84 (82.4%) Mean (SD) 20.1 (16.41) 25.2 (19.43) Median 14.918.8 Min-Max  2-105  1-91 Median time_(a)  22.18  26.01 95% CI oftime_(a) 16.58-35.82 18.58-31.32 0.2348 0.3571 Time to meaningful painrelief (N = 99) (N = 102) Subjects with relief, n (%)  35 (35.4%)  58(56.9%) Mean (SD) 50.7 (28.65) 50.3 (32.14) Median 45.5 46.1 Min-Max 13-114  11-152 Median time_(a) 106.30  70.22 95% CI of time_(a)84.72-NC 61.18-92.00 0.0080 0.0142 Evaluable Population Time toperceptible pain relief (N = 95) (N = 96) Subjects with relief, n (%) 67 (70.5%)  79 (82.3%) Mean (SD) 20.5 (16.54) 25.5 (19.57) Median 15.019.0 Min-Max  2-105  3-91 Median time_(a)  22.18  26.01 95% CI oftime_(a) 17.20-34.82 18.58-31.32 0.2833 0.4674 Time to meaningful painrelief (N = 95) (N = 96) Subjects with relief n (%)  34 (35.8%)  56(58.3%) Mean (SD) 50.8 (29.08) 51.5 (32.08) Median 45.4 47.1 Min-Max 13-114  11-152 Median time_(a) 106.30  70.22 95% CI of time_(a)84.72-NC 61.18-90.00 0.0058 0.0112 SD = standard deviation; Min =minimum; Max = maximum; CI = confidence interval; NC = not calculable_(a)Estimated using Kaplan-Meier product limit estimates including allsubjects in the given population.

It is noted that two of the sites did not cover the elapsed time displayon the stopwatches used to measure the meaningful and the perceptibletime to relief. All subjects at these sites were handled in this samemanner. A homogeneity analysis between sites showed no significantdifferences. While this protocol deviation is noted, common methodologyemploys both.

Severity of Adverse Events:

Table 12 summarizes treatment-related adverse events experienced byeither treatment group. The majority of the treatment-emergent adverseevents experienced during the study were classified by the Investigatoras mild or moderate in severity. One severe adverse event wasexperienced by one subject (1.0%) in the DPSGC 25 mg group. This subjecthad a severe event of vomiting that started on Day 1 and resolved thesame day without sequelae. The event was considered by the Investigatorto be possibly related to study drug.

Severe adverse events were experienced by 5 subjects (5.1%) in theplacebo group and included headache (2 subjects), coccydynia (1subject), vomiting (1 subject), and arthralgia (1 subject). Astatistically significantly smaller proportion of subjects in the DPSGC25 mg group (20.6%) experienced at least 1 treatment-emergent adverseevent compared to the placebo group (44.4%). Additionally, statisticallysignificantly smaller proportions of subjects in the DPSGC 25 mg groupexperienced nausea (7.8%) and pyrexia (0%) compared to subjects in theplacebo group (18.2% and 8.1%, respectively). The significantly greaterincidence of nausea observed in the placebo group compared with theDPSGC 25 mg group is most likely related to inadequate pain relief orassociated with the use of rescue medication. The significantly greaterincidence of pyrexia, as well as body temperature increased, observed inthe placebo group compared with the absence of pyrexia noted in theDPSGC 25 mg group is a result of the known antipyretic effect of NSAIDs.

No statistically significant differences were observed between thetreatment groups for the overall incidence of treatment-related adverseevents. Additionally, no statistically significant differences wereobserved between the treatment groups for the incidence of any specifictreatment-related adverse event.

TABLE 12 Treatment-Related Adverse Events Experienced by ≧2% of Subjectsin Either Treatment Group Treatment Group n (%) Placebo (N = (N = 99)102) p-value^(a) DPSGC 25 mg Number of Subjects with Any Event 15(15.2%) 14 (13.7%) 0.8422 Gastrointestinal Disorders 13 (13.1%) 12(11.8%) 0.8326 Abdominal Pain Constipation 2 (2.0%) 2 (2.0%) 1.0000 1(1.0%) 3 (2.9%) 0.6214 Diarrhoea 0 2 (2.0%) 0.4976 Nausea 9 (9.1%) 7(6.9%) 0.6102 Vomiting 5 (5.1%) 4 (3.9%) 0.7452 Investigations 2 (2.0%)0 0.2413 Body Temperature Increased 2 (2.0%) 0 0.2413 Nervous SystemDisorders 3 (3.0%) 3 (2.9%) 1.0000 Headache 2 (2.0%) 3 (2.9%) 1.0000Skin and Subcutaneous Tissue 2 (2.0%) 2 (2.0%) 1.0000 Disorders Pruritus2 (2.0%) 2 (2.0%) 1.0000

The present invention is not limited in scope by the specificembodiments described. Modifications of the invention in addition tothose described herein will become apparent to those skilled in the artfrom the foregoing description and the following claims.

1. A method of treating acute post-bunionectomy pain in a patient inneed of such treatment, said method comprising orally administering tothe patient a dose of between about 13 to about 25 mg of diclofenacpotassium in a dispersible liquid formulation about every 4 hours toabout 8 hours over a period of at least 24 hours, wherein the dailytotal amount of diclofenac potassium administered is less than or equalto about 100 mg.
 2. The method according to claim 1, wherein internalfixation is performed during bunionectomy.
 3. The method according toclaim 1, wherein the diclofenac potassium in the dispersible liquidformulation is administered about every 5 hours to about 8 hours.
 4. Themethod according to claim 1, wherein the diclofenac potassium in thedispersible liquid formulation is administered about every 6 hours. 5.The method according to claim 1, wherein the diclofenac potassium in thedispersible liquid formulation is administered over a period of about 30hours.
 6. The method according to claim 1, wherein the diclofenacpotassium in the dispersible liquid formulation is administered over aperiod of about 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168hours or seven days.
 7. The method according to claim 1, wherein theamount of the diclofenac potassium in the dispersible liquid formulationcomprises about 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg,16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 22.5 mg,or 25 mg, of diclofenac potassium.
 8. The method according to claim 1,wherein the administered amount of diclofenac potassium in thedispersible liquid formulation is effective for treating acute pain forabout 6 to about 8 hours after administration.
 9. The method accordingto claim 1, wherein the plasma concentration of diclofenac in a patientranges between about 670 to about 1500 ng/ml in less than 30 minuteswith the concomitant onset of relief of acute pain.
 10. The methodaccording to claim 1, wherein the administration of diclofenac potassiumin the dispersible liquid formulation results in immediate increase inplasma concentration of diclofenac characterized by T(max) of about 0.47hours.
 11. The method according to claim 1, wherein diclofenac issubstantially eliminated from plasma in the first 2 hours followingadministration.
 12. The method according to claim 1, wherein the amountof the diclofenac potassium in the dispersible liquid formulationcomprises about 25 mg of diclofenac potassium.
 13. The method accordingto claim 12, wherein the administration of diclofenac potassium in thedispersible liquid formulation results in an average 48 hour NPRS painscore of about 2.49.
 14. The method according to claim 12, wherein theadministration of diclofenac potassium in the dispersible liquidformulation results in a median time to onset of greater than or equalto 30% pain reduction of about 60 minutes in an 8 hour initial dosingperiod.
 15. The method according to claim 12, wherein the administrationof diclofenac potassium in the dispersible liquid formulation provides amedian time to onset of meaningful pain relief of about 70 minutes in an8 hour initial dosing period.
 16. The method according to claim 12,wherein the administration of diclofenac potassium in the dispersibleliquid formulation provides clinically significant analgesic efficacyfor about 6 hours.
 17. The method according to claim 12, wherein 25 mgof diclofenac potassium in the dispersible liquid formulation isadministered four times over a period of about 24 hours.
 18. The methodaccording to claim 1, wherein the diclofenac potassium in thedispersible liquid formulation is contained in a capsule.
 19. The methodaccording to claim 1, wherein the intensity of the acute pain rangesfrom mild to moderate, moderate to moderately severe, or moderate tosevere.
 20. The method according to claim 1, wherein no opioid isco-administered with the diclofenac potassium in the dispersible liquidformulation.